Huntington's Disease (HD) is an autosomal dominant neurodegenerative disorder characterized by chorea, dementia and personality disorder. Manifestations typically begin in middle-age and symptoms are progressive. There is no effective treatment for HD which follows an inexorable course leading first to total debilitation and then to death some 15 to 20 years after onset. HD places enormous economic and psychological burdens on its victim, the family and society as a whole. The Huntington's Disease Center Without Walls is a basic research center which has as its primary goals the discovery of the genetic defect causing HD, the elucidation of the mechanisms whereby it produces the clinical and pathologic features of the disorder, and the development of effective approaches to therapy. Now entering its tenth year, the Center is multidisciplinary, encompassing in a single cooperative program a broad range of research approaches including genetics, epidemiology, biochemistry, and neuroanatomy. This has been an exceedingly successful program which has significantly enhanced our knowledge of HD and altered the course of HD research. HD Center investigators have made seminal contributions to the genetics and epidemiology of HD, to the biochemical and neuropathological features of the disease, and to the organization of the basal ganglia. In particular, the dramatic demonstration in HD of the power of genetic linkage analysis with DNA markers helped to revolutionize the study of inherited human disease. The present renewal application reflects the high level of continued commitment of the investigators to achieving the Center's goals. Four projects and two core facilities are continued from the past grant period and two exciting new projects have been added. The proposed projects will attempt to define the molecular defect in HD (#1), to explore factors modifying its expression (#2), to investigate biochemical alterations in HD brain (E3), to study the response of surviving neurons to local cell death (#4), to create a genetic mouse model of HD (#5) and to generate a primate lesion model for the disorder (#6). The Center comprises a team of highly interactive investigators with a unique combination of expertise and considerable experience in HD. We are confident that the next five years will see tremendous strides towards achieving our goals of understanding the nature and consequences of the genetic defect, and of being able to provide an effective treatment for HD.